Systematic name M5958
Brief description Top genes down-regulated in liver tissue from mice with knockout of ZMPSTE24 [GeneID=10269].
Full description or abstract Zmpste24 (also called FACE-1) is a metalloproteinase involved in the maturation of lamin A (Lmna), an essential component of the nuclear envelope. Both Zmpste24- and Lmna-deficient mice exhibit profound nuclear architecture abnormalities and multiple histopathological defects that phenocopy an accelerated ageing process. Similarly, diverse human progeroid syndromes are caused by mutations in ZMPSTE24 or LMNA genes. To elucidate the molecular mechanisms underlying these devastating diseases, we have analysed the transcriptional alterations occurring in tissues from Zmpste24-deficient mice. We demonstrate that Zmpste24 deficiency elicits a stress signalling pathway that is evidenced by a marked upregulation of p53 target genes, and accompanied by a senescence phenotype at the cellular level and accelerated ageing at the organismal level. These phenotypes are largely rescued in Zmpste24-/-Lmna+/- mice and partially reversed in Zmpste24-/-p53-/- mice. These findings provide evidence for the existence of a checkpoint response activated by the nuclear abnormalities caused by prelamin A accumulation, and support the concept that hyperactivation of the tumour suppressor p53 may cause accelerated ageing.
Collection C2: curated gene sets
      CGP: chemical and genetic perturbations
Source publication Pubmed 16079796   Authors: Varela I,Cadiñanos J,Pendás AM,Gutiérrez-Fernández A,Folgueras AR,Sánchez LM,Zhou Z,Rodríguez FJ,Stewart CL,Vega JA,Tryggvason K,Freije JM,López-Otín C
Exact source Table 1S: Face1-liver change=D
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(show 2 gene sets from the same authors)
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Organism Mus musculus
Contributed by John Newman (University of Washington)
Source platform AFFY_MG_U74
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Version history 3.0: Renamed from ZMPSTE24_KO_DN

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